Peggy Scherle - Academia.edu (original) (raw)

Papers by Peggy Scherle

The Journal of dermatological treatment, Jan 14, 2016

Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, includi... more Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% f...

Bioorganic Medicinal Chemistry Letters, 2008

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1 0... more In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1 0 group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structureactivity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2 0 moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2 0 group effecting global conformational changes.

Journal of Medicinal Chemistry, Jun 1, 2009

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indo... more A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC 50 = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.

The Journal of Clinical Pharmacology, Dec 1, 2014

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor ... more Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.

Journal for ImmunoTherapy of Cancer, 2015

European Journal of Cancer Supplements, 2010

CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC... more CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC tissues by quantitative PCR. Finally, in order to characterize the phenotype of IL-17-positive cells, expression of IL-17, in combination with that of specific surface molecules, was analyzed on freshly excised CRC specimens by flow cytometry. Results: Frequencies of IL-17-producing cells, as well as IL-17 gene expression levels were significantly increased in tumour tissues as compared to autologous normal mucosa. IL-17-producing cells isolated from clinical specimens were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly,Foxp3 molecules. Accordingly, mRNA levels of genes encoding for cytokines favouring IL-17 acquisition by Foxp3+ T cells, including IL-6, IL-1beta, TGF-beta and IL-23, were found more elevated in CRC tissues as comparing to corresponding healthy mucosa. High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, with prolonged survival time in mismatch repair (MMR)-proficient, but not-deficient CRC. Moreover, the simultaneous CRC-infiltration by IL-17+ and Foxp3+ cells was significantly associated with improved survival in both MMR-proficient and -deficient tumours. Conclusions: Our data suggest that IL-17 produced by tumour-infiltrating either CD4+ or Foxp3+ cells may promote a benign clinical outcome in CRC.

The Journal of dermatological treatment, Jan 14, 2016

Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, includi... more Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% f...

Bioorganic Medicinal Chemistry Letters, 2008

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1 0... more In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1 0 group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structureactivity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2 0 moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2 0 group effecting global conformational changes.

Journal of Medicinal Chemistry, Jun 1, 2009

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indo... more A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC 50 = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.

The Journal of Clinical Pharmacology, Dec 1, 2014

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor ... more Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.

Journal for ImmunoTherapy of Cancer, 2015

European Journal of Cancer Supplements, 2010

CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC... more CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC tissues by quantitative PCR. Finally, in order to characterize the phenotype of IL-17-positive cells, expression of IL-17, in combination with that of specific surface molecules, was analyzed on freshly excised CRC specimens by flow cytometry. Results: Frequencies of IL-17-producing cells, as well as IL-17 gene expression levels were significantly increased in tumour tissues as compared to autologous normal mucosa. IL-17-producing cells isolated from clinical specimens were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly,Foxp3 molecules. Accordingly, mRNA levels of genes encoding for cytokines favouring IL-17 acquisition by Foxp3+ T cells, including IL-6, IL-1beta, TGF-beta and IL-23, were found more elevated in CRC tissues as comparing to corresponding healthy mucosa. High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, with prolonged survival time in mismatch repair (MMR)-proficient, but not-deficient CRC. Moreover, the simultaneous CRC-infiltration by IL-17+ and Foxp3+ cells was significantly associated with improved survival in both MMR-proficient and -deficient tumours. Conclusions: Our data suggest that IL-17 produced by tumour-infiltrating either CD4+ or Foxp3+ cells may promote a benign clinical outcome in CRC.